A significant number of tumors are classified as poorly or non-responsive to therapeutic drugs or radiotherapy. Increasing the chemotherapeutic dosage or radiation dose not only fails to improve the therapeutic response, but also contributes to the development of side effects and resistance to therapy. A great deal is now known about mechanisms of drug resistance in cancer cells. Despite the development of new targeted anticancer therapies, mechanisms that protect cells against cytotoxic compounds in mammals will continue to act as obstacles to successful treatment of cancer.
The design of cancer chemotherapy has become increasingly advanced in the last few years, yet there is no cancer treatment that is 100% effective against cancer mainly because of development of resistance to the anticancer drug. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumors. Frequently resistance is intrinsic to the cancer, but as therapy becomes more and more effective, acquired resistance has also become common. The most common reason for acquisition of resistance to a broad range of anticancer drugs includes expression of one or more energy-dependent transporters that detect and remove anticancer drugs from cells. Insensitivity to drug-induced apoptosis and induction of drug-detoxifying mechanisms are among other reasons underlying acquired anticancer drug resistance.
Studies on mechanisms of cancer drug resistance have yielded important information about how to circumvent resistance and to improve cancer chemotherapy and have provided additional knowledge for pharmacokinetics of many commonly used drugs. An ideal strategy would consist of the identification of anticancer agents able to act synergistically with standard treatments such as radiotherapy and chemotherapy and triggering the cell death preferentially in tumor cells.
Bone marrow malignancies are clonal disorders resulting from neoplastic transformation of hematopoietic stem or progenitor cells. Similar to their normal counterparts, transformed blood-forming cells remain dependent on signals from the hematopoiesis-regulating stromal environment for survival and proliferation. A review of the literature on stromal abnormalities in the leukemias, the myelodysplastic syndromes, and multiple myeloma reveals three principal mechanisms by which stromal derangements can contribute to the evolution of a neoplastic disease. In the simplest case, neoplastic blood-forming cells induce reversible changes in stroma function or composition which result in improved growth conditions for the malignant cells. In the second setting, functionally abnormal end cells derived from the malignant clone become an integral part of the stroma system, selectively stimulating the neoplastic cells and inhibiting normal blood cell formation. In the third condition, the emergence of a neoplastic cell population is the consequence of a primary stroma lesion characterized by inability to control regular blood cell formation (malignancy-inducing microenvironment).
The WHO classification system for hematopoietic tumors recognizes five categories of myeloid malignancies, including acute myeloid leukemia (AML), Myelodysplastic Syndrome (MDS), Myeloproliferative Neoplasm (MPN), MDS/MPN overlap, and PDGFR/FGFR1-rearranged myeloid/lymphoid neoplasms with eosinophilia. MDS and MPN are two groups of diseases in the family of bone marrow malignancies. MDS and MPN are not single diseases, but each encompasses a collection of hematopoietic and stem cell disorders.
The myelodysplastic syndromes, formerly known as preleukemia, are a diverse collection of hematological medical conditions that involve ineffective production (or dysplasia) of the myeloid class of blood cells. The WHO MDS category of diseases includes refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML). Patients with MDS often develop severe anemia and require frequent blood transfusions. In most cases, the disease worsens and the patient develops cytopenias (low blood counts) caused by progressive bone marrow failure. In about one third of patients with MDS, the disease transforms into acute myelogenous leukemia (AML), usually within months to a few years.
Hematopoietic cell diseases are thought to arise from mutations in the multi-potent bone marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and there is a significant increase in levels of apoptotic cell death in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. In MDS, if the overall percentage of bone marrow myeloblasts rises over a particular cutoff (20% for WHO classification, 30% for FAB classification) then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multi-step theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transform it into a cancer cell.
While recognition of leukemic transformation was historically important, a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. The myelodysplastic syndromes are all disorders of the stem cell in the bone marrow. In MDS, hematopoiesis is disorderly and ineffective. The number and quality of blood-forming cells decline irreversibly, further impairing blood production. Anemia is the most common cytopenia in MDS patients. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusions of packed red blood cells lead to iron overload, among other clinical risks.
The recognition of epigenetic changes in DNA structure in MDS has shown that proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth, and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, and thereby restore normal blood counts and retard the progression of MDS to acute leukemia.
Every year, between 15,000 and 45,000 patients in the US are diagnosed with MDS (Goldberg et al., 2010; Rollison et al., 2006). The age at which most patients are diagnosed is between 60 and 75 years old. Survival of patients with MDS is dependent on the severity of their disease; on average, it is 3 to 5 years after initial diagnosis (Ma et al., 2007). Most patients succumb to complications of cytopenias (uncontrollable bleeding or infections) or because the disease progresses to AML. Cases of AML that arise from prior MDS do not respond well to chemotherapy and have a poor prognosis.
There have also been many cases of MDS/MPN overlap. MDS/MPN overlap disorders come in many variations: as a true overlap condition at initial presentation, with evidence of dysplasia of cellular elements and myeloproliferative components (such as fibrosis, hypercellularity, or organomegally); as MDS that takes on MPN features over time; or, conversely, as an MPN in which progressive marrow dysplasia develops. These disorders include chronic myelomonocytic leukemia (CMML), atypical (BCR-ABL1 negative) chronic myeloid leukemia, juvenile myelomonocytic leukemia, and MDS/MPNu1 as seen in this patient. Some MDS/MPN cases have JAK2 mutations (such as the provisional entity, refractory anemia with ring sideroblasts and thrombocytosis). The proliferative components of these disorders are related to abnormalities in the RAS/MAPK signaling pathways, and approximately 50 percent are associated with TET2 mutations.
While investigational drug therapies exist, there is currently not a curative drug treatment for most hematological cancers. Current treatment strategies for hematopoietic cancers include:
1) Allogeneic stem cell transplantation. This, however, is not a good treatment option for patients with lower-risk MDS because it usually shortens their survival. This treatment is generally reserved for patients 55 years and younger with more severe disease and who can withstand the rigors of the procedure. Although bone marrow transplant has resulted in long-term disease-free survival in some patients with MDS, the morbidity and mortality of this approach remains high. Many patients are not candidates for such an approach because of their age or other health issues. While bone marrow transplantation clearly has a role in the treatment of MDS, the decision to proceed to transplantation is not always easy and the optimal approach has not been clearly defined (Luger and Sacks, 2002).
2) Chemotherapy. These therapies result in severe reactions in the patients which lead to resistance to the therapy.
3) Erythropoiesis-stimulating agents (ESAs): ESAs encourage the body to make more red blood cells. ESAs have been used in managing anemia in MDS patients. However, recent data has raised safety concerns with the use of ESAs in oncology (Bennett et al, JAMA, 2008, 299, 914). The U.S. Food and Drug Administration has not approved ESAs for MDS because of the lack of randomized clinical studies and concerns about ESA safety of in patients with solid tumors, such as breast cancer or lung cancer. But research has not shown that these drugs increase the risk of AML in MDS, and they may improve survival. The work is currently in progress to investigate clinical reasons as to why some patients respond to ESAs for a while, but then have a relapse.
4) Blood transfusion. Anemia is a common occurrence in MDS patients, with more than 50% patients exhibiting anemia when first diagnosed with MDS. Up to 90% will develop anemia during progression of the disease and 80% will require transfusions to control the disease process. Chronic red blood transfusions to treat anemia generally result in iron overload, which is damaging to heart, liver and other tissues. Symptoms go unnoticed until serious organ damage occurs resulting in hepatic failure, heart disease and bone marrow suppression. Chronic transfusion dependency and iron overload are independent predictors of decreased survival and increased transformation to acute myeloid leukemia (AML).
5) DNA methyltransferase inhibitors. Hypomethylating agents or demethylating, agents, for example azacytidine (Vidaza®, decitabine (Dacogen®) and the 5q31 clone suppressor lenalidomide (Revlimid®), help the bone marrow of patients with hematopoietic cancers to function normally and kill unhealthy cells. The most common adverse events associated with DNA Methyltransferase inhibitors are injection-site reactions, gastrointestinal events and hematologic events. Other adverse reactions included diarrhea, nausea and vomiting. Currently, several other new agents are under investigation for the treatment of hematological cancers. These include HDAC inhibitors (phenyl butyrate, valproic acid, MS-275, MGCD0103, vorinostat); Farnesyltransferase inhibitors (topifarnib, lonifarnib); TNF inhibitor Embrel®, nucleoside analogs, retinoids and glutathione derivatives.
The most important goals in hematopoietic cancers, in addition to prolonging survival, are development of higher hematologic responses and improvement in quality of life. Since hematopoietic cancers are biologically complex heterogeneous diseases, a single treatment strategy may not work for all patients. Accordingly, none of the aforementioned therapies are curative, and patients ultimately fail to respond over time. This failure of response leads to a poor prognosis where the average life expectancy is within few months. Thus, there is an urgent need for new treatments for patients with hematopoietic and/or hematological cancer, whose disease no longer responds to the existing drugs. Development of new treatment strategies including effective combination therapies has become critical in cancer treatment.
Accordingly, there is a long felt need in discovering new treatment strategies that might be effective in people with hematological cancer. Because of a lack of available treatments for myelodysplastic syndrome and acute myeloid leukemia, and the toxicity and side effects associated with existing agents, the need exists for new therapies in the treatment of these diseases, particularly therapies that have greater potency and lower toxicity and/or activity across a broader spectrum of cell types.
The present invention as disclosed and described herein provides therapeutic methods and compositions that can be used in combination with chemotherapy or radiotherapy to treat or ameliorate symptoms of hematological cancers such as MDS, and/or prolonged survival of cancer patients.